B5 - Haemolytic anaemia and haemoglobinopathies Flashcards

1
Q

haemolytic anaemia

A
  • Red cell destruction
    ○ Increased bilirubin (haem breakdown)
    ○ Increased LDH - lactate dehydrogenase which is liberated from red blood cells
    ○ Reduced haptoglobins (Hb-haptoglobin complex) - haptoglobin is consumed when binding with haemoglobin
    • Evidence of damaged red blood cells
      ○ Spherocytes
      ○ Fragmented red blood cells (schistocytes) - occurs in mechanical fragmentation in intravascular haemolysis
    • Evidence of increased RBC production
      ○ Reticulocytosis (polychromasia) - typically larger, purple immature cell
      ○ Nucleated red blood cells - a step in red blood cell maturation prior to reticulocyte (reticulocyte has nucleus extruded)
      ○ Occurs with normal bone marrow function
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2
Q

clinical features of haemolytic anaemia

A
  • Anaemia - tiredness, fatigue etc.
    • Breathless/light headedness
    • Jaundice: bilirubin in plasma
    • Pigment gallstones (composed primarily of bilirubin) may occur
    • Splenomegaly (common)
    • Ankle ulcers, usually with people with sickle cell
    • Expanded bone marrow - response to blood cell breakdown by increasing erythropoiesis
    • Aplastic crises: parvovirus
    • Megaloblastic anaemia: folate deficiency (used up)
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3
Q

hereditary causes of haemolytic anaemia

A

○ Membrane defect: hereditary spherocytosis
○ Enzyme defect: G6PD deficiency
○ Globin chain defect: haemoglobinopathies

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4
Q

acquired causes of haemolytic anaemia

A
○ Immune haemolytic anaemia
		○ Fragmentation haemolysis - thrombotic thrombocytopenic purpura (TTP)
		○ Oxidative haemolysis 
		○ Liver disease (spur cell anaemia)
		○ Infections, renal disease, etc.
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5
Q

hereditary spherocytosis

A

§ Most common inherited haemolytic anaemia
§ Autosomal dominant with variable severity
§ Defect in structural RBC membrane protein
□ Spectrin, ankyrin, band 3
§ RBC less deformable and lose membrane when passing through spleen
□ Lose surface area
§ Red cells become spherical, rigid and then destroyed
§ Fluctuating anaemia and jaundice
§ Splenomegaly and pigment gall stones

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6
Q

hereditary spherocytosis lab features

A

□ Spherocytes on blood film
□ Polychromasia due to increased reticulocytes (bone marrow response)
□ Negative DAT (direct antiglobulin test)
® Test looking for evidence of immune haemolysis and the presence of antibodies that want to bind red blood cells and destroy them, would be positive in immune haemolysis)
□ Positive EMA (band-3) (probe looking for band 3 protein)
® Flow cytometric test
® Specialised assay that identifies target structures or proteins on cells by creating a fluorescent probe that finds a particular structure
® Eosin-5-malemide binds to band-3 protein
® Probe tends to be reduced or deficient because band-3 is lacking
® Gold standard

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7
Q

direct antiglobulin test

A

® Test looking for evidence of immune haemolysis and the presence of antibodies that want to bind red blood cells and destroy them, would be positive in immune haemolysis)

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8
Q

EMA (band-3) (probe looking for band 3 protein)

A

® Flow cytometric test
® Specialised assay that identifies target structures or proteins on cells by creating a fluorescent probe that finds a particular structure
® Eosin-5-malemide binds to band-3 protein
® Probe tends to be reduced or deficient because band-3 is lacking
® Gold standard

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9
Q

treatment for hereditary spherocytosis

A

□ Splenectomy - if the haemolysis is pronounced, severe cases
□ Folic acid, used to quickly so needs to be replenished otherwise they will have haemolytic and megaloblastic anaemia at the same time
□ Chlocystectomy: removal of the gall bladder to prevent bilirubin gall stones

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10
Q

○ Hereditary Elliptocytosis

A
§ Autosomal dominant 
			§ Milder than HS 
			§ Many asymptomatic 
			§ Mutations in spectrin 
			§ 10% have haemolysis 
			§ Elliptical red blood cells 
			§ Variants 
				□ Hereditary pyro-poikilocytosis 
				□ South east Asian ovalocytosis
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11
Q

G6PD deficiency

A

§ Glucose-6-phosphate dehydrogenase deficiency
§ Enzyme in the hexose monophosphate shunt which generated reducing power as NADPH
§ G6PD deficiency: most common red cell enzyme disorder worldwide
§ Gene-X linked chromosome: males more likely to be effected
§ G6PD deficiency
□ RBC susceptible to oxidative stress - causes haemolysis
□ When not subject to oxidative stress, they’ll be fine
□ Triggers of oxidant haemolysis: drugs, fava (broad) beans, infection, hypoxia
□ Intravascular haemolysis (self limiting)
□ Oxidised Hb removed
□ Blood film: bite or blister cells - looks like a bit has been taken out of them due to denatured haemoglobin being removed by macrophages
® Due to oxidative stress denatured haemoglobin (heinz bodies) are formed and macrophages remove them
□ Pooling to one side of the cell - hemighost cells
□ Treatment
® Remove/stop/treat offending agent
® Treat infection
® Transfuse if necessary - most people will not need this
□ Normal blood count between crises

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12
Q

2 enzyme defects leading to haemolytic anaemia

A

G6PD deficiency, pyruvate deficiency

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13
Q

G6PD deficiency blood film

A

□ Blood film: bite or blister cells - looks like a bit has been taken out of them due to denatured haemoglobin being removed by macrophages
® Due to oxidative stress denatured haemoglobin (heinz bodies) are formed and macrophages remove them
□ Pooling to one side of the cell - hemighost cells

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14
Q

triggers of oxidation in G6PD enzyme deficiency

A

drugs, fava (broad) beans, infection, hypoxia

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15
Q

G6PD inheritance

A

X-linked

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16
Q

Heinz bodies

A

denatured haemoglobin formed due to G6PD deficiency

17
Q

pyruvate kinase

A

§ Glucose is metabolised in RBC by anaerobic glycolysis
§ Embden-Meyerhof pathway
§ Pyruvate kinase is the enzyme that catalyses the final step of glycolysis and is required to make ATP
§ G6PD is more common

18
Q

pyruvate kinase deficiency

A

□ Inherited enzyme defect
□ Lack of PK: insufficient ATP made
□ Rigid cell membrane and cell death
□ Haemolytic anaemia
□ Splenectomy partly improves anaemia
□ Autosomal recessive inheritance
□ Variable clinical presentation
® Mild: occasional compensated haemolysis
® Severe: can present in neonatal period with failure to thrive, splenomegaly
□ Prickles on RBC

19
Q

diagnosing pyruvate kinase deficiency

A

pyruvate kinase assay

20
Q

○ Structural haemoglobinopathies

A

§ Abnormal globin chain structure

§ HbS (sickle cell anaemia); HbE (Thailand); HbC (africa)

21
Q

Thalassemia

A

○ Thalassemia
§ Reduced production of a or b globin chains
§ SE Asia (alpha) and Mediterranean (beta)
§ Microcytic anaemias

22
Q

B thalassaemia

A
§ Mediterranean or SE Asia 
			§ Mutations in the B globin gene 
			§ Reduced b chain production 
			§ Homozygous (thalassemia major)
				□ Present at 3-6 months
				□ Sever anaemia, transfusion dependant, bone marrow transplant
			§ Heterozygous (thalassaemia minor)
				□ Asymptomatic
23
Q

A thalassaemia

A

§ Common in SE Asia
§ 4 a globin genes on chromosome 16 aa/aa
§ Gene deletions 1,2,3, or 4
□ -a/aa and -a/-a thalassaemia minor
□ –/aa thalassaemia minor
□ –/-a haemoglobin H disease
□ –/– Hb barts hydrops fetalis (not compatible with life)

24
Q

Bart’s hydrous fetalis

A

§ No a chains

25
Q

HbS

A

occurs in African ethnicities
□ HbS forms crystals: sickle shapes RBC
□ Sickling crisis: painful, occluded vessels - happen during low oxygen levels
□ Chest pain, bone pain, tissue infarction, stroke
□ ‘auto-splenectomy’: infarction of spleen - spleen gradually dies off
□ Sickle shapes don’t pass through microvasculature very well
□ Haemolysis - anaemia

26
Q

○ Structural haemoglobinopathies

A

Point mutations causing a structural abnormality in a globin chain

27
Q

HbE

A

Thailand, target cells, low MCV, common

28
Q

HbC

A

west Africa, target cells

29
Q

auto Immune Haemolytic Anaemia

A

○ Haemolysis due to antibodies directed at RBC
○ Auto-immune haemolytic anaemia
§ Derived from antibodies made by one’s own body
§ Auto antibody directed at own red blood cells
§ Causes: idiopathic/unknown
§ Disease associations: b cell lymphoma or lymphoid leukemias, autoimmune diseases eg. Lupus

30
Q

auto immune haemolytic anaemia blood film

A

§ Blood film
□ Spherocytes and polychromasia due to reticulocytosis on PB film
Presence of nucleated red blood cells and associated disease eg. Leukaemia

31
Q

auto immune haemolytic anaemia direct anti-globulin test

A

§ Positive direct antiglobulin test (DAT)
□ Marker of the presence off antibodies that want to bind and destroy red blood cells
□ Blood sample from patient is incubated with antihuman antibodies (Coombs reagent) - if the RBCs agglutinate - this means antihuman antibodies are forming links with antibodies bound to cell surface of RBCs - positive result

32
Q

auto immune haemolytic anaemia treatment

A

§ treatment: immunosuppression (corticosteroids to reduce antibody production); treat cause (lymphoma, leukaemia, auto-immune disease), splenectomy in some cases, transfusion may be required if severe

33
Q

Allo-immune haemolytic anaemia

A

§ Antibody made by 1 individual reacts with RBC of another (donor)

34
Q

§ Acute haemolytic transfusion reaction

A

□ Transfuse wrong/incompatible blood (lab error)

35
Q

§ Delayed haemolytic transfusion reaction

A

□ Low level antibody in donor serum not found in testing, driving low level haemolytic reaction over time

36
Q

§ Haemolytic disease of the newborn

A

□ Allo-immune haemolytic anaemia
® Transplacental passage of maternal RBC antibodies
® Maternal antibodies destroy fetal RBC
® Doesn’t effect first pregnancy, but will effect second
® Usually Rh(D) negative mother & Rh(D) positive fetus
◊ Anti-D (antibodies) made by mother in first pregnancy when exposed to D antigen
◊ Subsequent pregnancy: maternal anti-D crosses the placenta, binds to and destroys fetal Rh(D) positive RBC
◊ Give anti-D injections to the mother at staggered phases during pregnancy

37
Q
  1. Acquired: fragmentation haemolysis
A

○ Mechanical damage to RBCs
○ ‘Micro angiopathic haemolytic anaemia’ - defect in the blood vessels
§ Red blood cells get damaged as they pass through due to the defect in the blood vessels
§ Any impediment to smooth passage of red blood cells
○ Red cells exposed to an abnormal surface
§ Small blood vessels
§ Heart valve, pinhole lesion in heart
§ Fibrin strands in the vasculature
§ Damaged small blood vessels
§ Any impediment to smooth passage of red blood cells
○ Red cell fragmentation
§ Leads to anaemia
§ Schistocytes (fragments) on film
§ Intravascular haemolysis (inside BV)

38
Q

‘Micro angiopathic haemolytic anaemia’

A

defect in the blood vessels
§ Red blood cells get damaged as they pass through due to the defect in the blood vessels
§ Any impediment to smooth passage of red blood cells

39
Q
  1. Other Acquired Haemolytic Anaemia
A

○ Liver disease (spur cell anaemia) and renal failure alter the RBC membrane
○ Infections: can be inside RBC eg. Malaria (malarial parasites like to live inside RBC)
○ Infections and haemolytic anaemia
§ Severe bacterial sepsis
□ Disseminated intravascular coagulation which results in microangiopathic haemolytic anaemia
§ Malaria
§ Clostridium welchii
□ Spherocytic